David Horne, MD, MPH

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You want me to take how many months of
medication? Advising your patient on risks vs.
benefits of LTBI treatment

• David Horne, MD, MPH
• Division of Pulmonary and Critical Care
• Harborview Medical Center
• University of Washington

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Outline

• LTBI Definition, Guideline History
• Risks Progression to Active TB
• Risks Treatment
• Cost vs. Benefit
• Discussing with your patient
• Caveat examples use TST isoniazid

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What is Latent TB Infection?

• Evidence of prior exposure to Mtb, based on
  interrogation of T cells, without clinical,
  radiographic or microbiologic evidence of active
  disease
• latency should not imply dormancy of Mtb
  without metabolic activity
• TB historically 2-state condition active TB or
  latent infection

Spectrum ???
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TB Outcomes after Exposure

• Dogma ? Lifetime risk of reactivation TB 5-10
• Patient May be substantial over- or
  under-estimate of risk

Small NEJM 2001
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LTBI Screening Treatment Balance

• Only 10 of individuals with positive LTBI test
  will progress to active TB
• Adverse effects related to treatments
• Poor completion rates

• 70 of TB cases in U.S. due to reactivation
• LTBI treatment is effective

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LTBI Screening Recommendations A History

• Isoniazid - introduced in 1952 for treatment of
  active TB
• In 1955, use expanded to include treatment of
  LTBI
• Campaign for widespread prophylaxis instituted
  (genl popln screening)
• Early 1970s, liver injury deaths due to
  isoniazid hepatotoxicity
• 1974, ATS recommended restricting prophylaxis to
  lt 35 years of age unless increased risk for
  activation
• Ensuing years, further decrease in INH use among
  young individuals
• 2000 Guidelines -Targeted Tuberculin Testing 
• INH-related morbidity lower than believed
• Focus on testing/treatment of individuals at high
  risk of progression to active TB

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LTBI recommendations

• Targeted tuberculin testing for LTBI identifies
  persons at high risk for developing TB who would
  benefit by treatment of LTBI, if detected.
• 2000 ATS Guidelines, Targeted Tuberculin Testing
  and Treatment of LTBI

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Targeted Testing (2000 Guidelines)

• Recent Infection with M. tuberculosis
• Close contacts
• Recent immigrants from areas with high TB rates
  (lt 5 years)
• Known converters
• Children younger than 5 years
• Homeless, IVDU, institutional setting exposures
• Increased Risk for Progression
• HIV infection
• CXR suggestive of old TB (fibrotic)
• Medical conditions diabetes, silicosis,
  dialysis, cancer, underweight
• Medically immunosuppressed

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Targeted Testing Broad Identification

• 22 y/o Filipino woman, immigrated 3 years ago
  TST 15mm, CXR normal
• Same person, but 42 years of age immigrated 3
  years prior
• Same person, but 72 years of age immigrated 3
  years prior

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Updated Risk Estimates for Active TB
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Risk of TB Comparing Estimates
RR Estimates, ATS Guidelines 10-25
2-4 30 2-5
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Risk Active TB Age
Horsburgh, NEJM 2004 350
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Risk of Active TB
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Risk of Active TB Immigration

• Targeted Testing includes recent (lt 5 years)
  immigrants from areas with high TB rates
• New arrivals from high-incidence countries
  hypothesized to arrive with high-risk early
  latency because of ongoing exposure
• High TB rates immediately after arrival assumed
  to indicate that reactivation risk declines with
  time in US
• U.S. TB cases 63 among foreign born (2012)

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U.S. TB Cases Different Trends by Birth
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TB Case Rates Remain Elevated in Foreign Born for
Years after Immigration
Cain JAMA 2008
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Changes in Reactivation Risk Among Immigrants

• To address marked difference between 1st year and
  subsequent years following immigration, Walter et
  al looked at immigration from Philippines
• Separated out those who had abnormal immigration
  CXR and developed TB in 1st year (presumed active
  inactive TB)
• Among those with normal CXRs There was no
  decline in TB reactivation over 9-year period
  (32/100,000)

Walter AJRCCM 2014
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Changes in Reactivation Risk Among Immigrants
Walter AJRCCM 2014
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Durable Reactivation Risk Differs by Region of
Origin
Cain AJRCCM 2007
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Seattle-King County Experience
PHSKC Annual Report on TB, 2010
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Risk of Active TB - Summary

• Major Risk Factors include
• Age
• HIV
• CXR upper lobe fibronodular disease
• Moderate Risk
• Recent Conversion
• Among immigrants risk varies by region of origin
  and may persist

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Treatment Risks

• Of INH adverse effects, drug-induced liver injury
  (DILI) most feared
• Significant transaminase elevation 0.1-0.6
• RFs age, EtOH, ethnicity
• USPHS study from 1970s still quoted 20 - 34
  years 0.3, 35-49 1.2, 50 64 2.3, gt65
  years 4.6
• Seattle study 0.28 of gt65 years
• 2004-0817 severe adverse events associated with
  INH
• 5 died, 5 liver txpestimated 291,000-433,000
  treated annually
• Other LTBI regimens likely safer than INH

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Cost-Benefit the Societal Perspective

• Older studies have supported screening and
  treatment of LTBI as cost-effective for all risk
  groups (e.g. Rose Arch Int Med 2000)
• Recent study using revised estimates of LTBI
  progression, completion rates of LTBI identified
  cost effectiveness for certain risk groups (Linas
  AJRCCM 2011)

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Cost-Benefit the Societal Perspective
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Assessing your patients risk
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Individual Risk Stratification Online TST/IGRA
Interpreter www.tstin3d.com
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TB Risk Estimates tstin3d.com

• 22 y/o Filipino woman, immigrated 3 years ago
  TST 15mm, CXR normal?5.8 lifetime risk
• 42 y/o Filipino woman, immigrated 3 years ago
  TST 15mm, CXR normal?3.8 lifetime risk
• 42 y/o Filipino woman, immigrated 3 years ago
  TST 15mm, DM (Hgb A1c 7.9)? 10.6 lifetime risk
• 42 y/o Filipino woman, immigrated 3 years ago
  TST 15mm, CXR shows stable RUL fibronodular
  changes ? 47.6 lifetime risk
• 73 y/o Filipino woman, immigrated 3 years ago
  TST 15mm, CXR normal? 0.7 lifetime risk

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Risk Estimates - tstin3d.com

• May overestimate individual risk of TB
  progression
• Assumes baseline annual risk of TB 0.1 in
  healthy persons
• If patient is recent close contact, then risk of
  TB is 5 for the first 2 years and 0.1
  thereafter
• Horsburgh differences
• Same baseline risk, lower risks following new
  conversion by age group
• Lower risks for progression in co-existing
  conditions
• May overestimate INH DILI risk

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Risk Estimates - tstin3d.com

• May overestimate individual risk of TB
  progression
• Assumes baseline annual risk of TB 0.1 in
  healthy persons
• If patient is recent close contact, then risk of
  TB is 5 for the first 2 years and 0.1
  thereafter
• Horsburgh differences
• Same baseline risk, lower risks following new
  conversion by age group
• Lower risks for progression in co-existing
  conditions
• May overestimate INH DILI risk

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Risk Estimates - tstin3d.com
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Shared Decision Making Risk Stratification
Advising Your Patient

• At what level of risk for TB progression should
  you recommend LTBI Treatment?
• No guideline recommendations
• Some experts use cut-offs of 3 risk or 5 risk
• Based on USPHS study estimated risk of
  age-related INH toxicity (50 64 2.3, gt65
  years 4.6 percent)
• Remember Seattle study, 0.28 of gt65 years

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Shared Decision Making

• Firm cut-off will not be appropriate for all
  situations
• Individual costs involve more than DILI
• Discuss with patient using available tools
• Patients need to be motivated to actually
  complete treatment
• Completion rates lt 50 in many series

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In Summary

• Risk for progression to active TB varies by
  patient factors
• Age of patient important in calculating life-time
  risk
• Duration of risk following immigration likely
  longer than previously stated region of origin
  may impact risk

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In Summary

• Better tools are available for risk assessment
  and may aid clinicians and patients in
  considering LTBI treatment
• To treat or not to treat? Have a discussion
• Alternative Regimens are increasingly popular
  improved completion rates
• LTBI guidelines overdue for update

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Questions/Comments?